title: Macrophage migration is controlled by Tribbles 1 through the interaction between C/EBPβ and TNF-α.
abstract: In mammals, three Tribbles gene family members have been identified, Tribbles 1, 2 and 3 (Trib1, Trib2 and Trib3). All family members are considered to be pseudokinases in that they contain domains homologous to serine/threonine kinase catalytic cores, but they lack several conserved residues in the ATP-binding pocket. Trib1 is implicated in the inflammatory response pathway through its ability to regulate mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB) and CCAAT Enhancer Binding Protein (C/EBP). However, its role in macrophages function is unknown. Here, we investigated the functional role of Trib1 in Toll-like receptor-mediated inflammatory responses to IFN-γ in RAW264.7 cells. In gene knock-down experiments in macrophages using small interfering RNAs targeted to Trib1, it was observed that TNF-α production was increased following treatment with IFN-γ and/or TLR2 ligands. Finally, Trib1-silenced macrophages failed to show MCP-1 induced chemokinesis and indicating involvement of Trib1 in controlling of macrophage migration. This work demonstrates that Trib1 contributes to the pro-inflammatory response caused by TLR2 ligands and controls macrophage migration as well as being a biomarker in macrophage-related diseases in both human and veterinary medicine.
authors.affiliation: Royal (Dick) School of Veterinary Studies and Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK. crayfish1115@gmail.com
authors.forename: Yi-Hsia
authors.initials: YH
authors.lastname: Liu
authors.forename: Karen A L
authors.initials: KA
authors.lastname: Tan
authors.forename: Ivan W
authors.initials: IW
authors.lastname: Morrison
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lamb
authors.forename: David J
authors.initials: DJ
authors.lastname: Argyle
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D055785:Gene Knockdown Techniques; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology* / Q000502:physiology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C474830:TRB3 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C523598:Trib1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases
keywords: C/EBP; CCAAT enhancer binding protein; ERK; Inflammation; Innate immunity; MARK; MCP-1; Migration; NF-κK; Pro-inflammatory cytokines; TLR2L; Toll-like receptor 2 ligand; Trib; Trib1; Tribbles; Tribbles 1; extracellular signal-regulated kinase; mitogen-activated protein kinase; monocyte chemotactic protein-1; nuclear factor kappa B